Page 104 - Clinical variability in Noonan syndrome with emphasison ear and eye

CHAPTER 7
General
Noonan syndrome is characterized by a wide spectrum of features and symptoms. Different symptoms and characteristics are studied and described in literature, some more frequent than others. Distinctive facial symptoms are described frequently, including external ear and external ocular characteristics. Studies for hearing impairment and ocular manifestations in Noonan syndrome are found less frequent in literature.
The first gene responsible for Noonan syndrome was found in 2001. Many molecular studies are performed since. In approximately 80% of the clinically diagnosed Noonan syndrome patients, a germline mutation in one of the known Noonan syndrome genes is found. There is a broad phenotypic range and genotype-phenotype studies show large variability, also within families. To gain more insight in the intra-familial phenotypic expression we studied a large Noonan syndrome family with a new SOS1 mutation.
The aim of this thesis was to improve the clinical knowledge and recognition of Noonan syndrome. We performed new studies to investigate hearing impairment and ocular characteristics in Noonan syndrome and we described a large Noonan syndrome family due to a new SOS1 mutation to get more insight in genotype-phenotype correlations within one family. With better insight in the hearing problems and ocular features including visual impairment, healthcare for the Noonan syndrome patients can be improved. Furthermore, genotype-phenotype correlations will help in diagnosing Noonan syndrome and will improve the healthcare and follow-up throughout their lives.
Genotype, phenotype and correlations
Until 2001 Noonan syndrome was solely diagnosed by clinical characteristics. In 2001 the PTPN11 gene was the first gene discovered to cause Noonan syndrome (1). As, in the moment, only in about three-quarter of the Noonan syndrome patients the diagnosis can be confirmed by one of the known germline mutations, Noonan syndrome still is a clinical diagnosis. Van der Burgt described a scoring system for the clinical diagnosis of Noonan syndrome in 1994, with an update in 2007 (2). The clinical diagnosis is preferably confirmed by a mutation in the RAS/MAPK pathway.
In recent years more studies with genetic testing are performed and genetic testing for diagnosing Noonan syndrome is becoming more prominent, also in individuals and studies without a clear clinical diagnosis. Due to the high number of genes causing
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